- Email: [email protected]
Electrodermal activity in schizophrenia: a quantitative study using a short interstimulus paradigm
Electrodermal Activity in Schizophrenia: A Quantitative Study Using a Short Interstimulus Paradigm Chong L. Lim, Evian Gordon, Anthony Harris, Homayoun Bahramali, Wai M. Li, Barry Manor, and Chris Rennie Background: Electrodermal activity in response to short interstimulus interval (ISI) stimulation allows aspects of information processing to be examined, but such paradigms cause skin conductance responses (SCRs) to overlap. A signal decomposition method was developed and employed to score the overlapped SCRs. This is the first application of the method to the study of schizophrenia. Methods: Electrodermal activity of 30 medicated patients with schizophrenia and 50 normal controls was obtained using a conventional auditory oddball paradigm with an ISI of 1.3 sec. Tonic skin conductance level (SCL), phasic SCRs, SCR temporal dynamics, and a range of SCR variables in response to target tones were examined. Results: The schizophrenic group showed reduced response rate, proportion of responders, SCR amplitude, rise time, peak latency, and steady-state response amplitude over the trial compared with controls. There were no between-group differences in SCL or SCR onset time. Conclusions: The combined use of a conventional short ISI paradigm and the new SCR scoring method demonstrated new facets of electrodermal hyporeactivity in medicated patients with schizophrenia. The hyporeactivity could not be attributed to changes in tonic arousal or dysfunctions in peripheral sympathetic nerve conductance. Biol Psychiatry 1999;45:127–135 © 1999 Society of Biological Psychiatry Key Words: Schizophrenia, autonomic, skin conductance, phasic skin conductance response, tonic skin conductance level
Introduction
D
iscovery of electrodermal activity (EDA) in humans by Fe´re´ in 1888 (Bloch 1993) and subsequent experiments in cats (Darrow 1927; Wang and Lu 1930; Wang
From the Department of Neurology (CLL) and Cognitive Neuroscience Unit, Department of Psychiatry (EG, HB, WML, BM, CR), University of Sydney and Westmead Hospital, Sydney, Australia; and Department of Psychiatry, Nepean General Hospital, Penrith, Australia (AH). Address reprint requests to Chong Lee Lim, Neurology Department, Westmead Hospital, Westmead 2145, Australia. Received January 7, 1997; revised July 11, 1997; revised January 26, 1998; accepted February 3, 1998.
© 1999 Society of Biological Psychiatry
1964) and monkeys (Kimble et al 1965) elucidated some of the central networks underlying electrodermal activity (Roy et al 1993; Sequeira and Roy 1993). This basic research fueled numerous psychophysiological studies; a large number of these studies have focused on schizophrenia. EDA findings in schizophrenia include hyporeactivity (a higher incidence of about 40% nonresponders compared with 5–10% of normals), and faster habituation and recovery. More recent reviews highlight slow habituation and short recovery time in patients with schizophrenia, while noting some conflicting results (Boucsein 1992, pp 244 –248; Venables 1993). The lack of consistent findings in schizophrenia has been exacerbated by the heterogeneity of the disorder and differences in the paradigms employed. A small change in task instruction (Iacono and Lykken 1979), stimulus pa¨ hman 1981), and significance (Bernstein et al rameters (O 1982) can alter the proportion of nonresponders. Many previous studies used nontask paradigms with long interstimulus intervals (ISIs). Paradigms requiring attention and performance, on the other hand, may result in a higher proportion of responders and responses to stimuli. The conventional event-related potential (ERP) paradigms using short ISI stimuli have been extensively used to explore possible dysfunctions in information processing in schizophrenia (for review see Pritchard 1986). Successful use of such conventional ERP paradigms in an electrodermal study might elicit a larger proportion of responders and would also facilitate future concurrent study of central and autonomic activity. In this study, we applied a new method to score overlapping skin conductance responses (SCRs), to the study of task-relevant target SCRs in a conventional auditory oddball paradigm with short ISIs. Abundant SCR responses were obtained using this paradigm, and they frequently overlapped (Figure 1), presenting a difficult measurement task. We have recently developed a fourparameter sigmoid-exponential SCR model (Lim et al 1997), which employs a curve-fitting method to decompose response overlaps into their constituent parts. The software implementation of the method is known as SCORES (Skin Conductance Response Evaluation Sys0006-3223/99/$19.00 PII S0006-3223(98)00056-0
128
C.L. Lim et al
BIOL PSYCHIATRY 1999;45:127–135
Figure 1. Skin conductance traces during the test period of a normal subject (top panel) and a patient with schizophrenia (bottom panel). These traces were complex, consisting of numerous responses to target tones that considerably overlapped.
tem), and a brief description of how it works is provided. SCORES scans each response complex associated with each target stimulus and iteratively optimizes the model parameters so as to minimize the mean square difference between the actual and the constructed curves. The fitted curve has been shown to be almost indistinguishable from the actual raw response complex (the top two superimposed SCR curves in Figure 2). For further details please refer to the Methods section and to the previous publication about this method (Lim et al 1997). In this exploratory study, we predicted a high proportion of responders and responses to stimuli in both groups, but diminished response amplitude and delayed latency and recovery time in the schizophrenic group compared with controls.
Methods and Materials Subjects Thirty subjects (mean age 5 35.4, SD 5 9.5 years) with schizophrenia (DSM-III-R and ICD 10) as diagnosed by a psychiatrist using the Composite International Diagnostic Interview (CIDI) were compared with 50 normal control subjects. Subjects with schizophrenia were recruited from mental health services and a schizophrenic support group. All subjects with schizophrenia were medicated. Since clozapine, the atypical antipsychotic, has been reported to have a marked attenuation effect on electrodermal activity (Zahn and Pickar 1993), the 30 patients (SZ) were separated into two groups—25 patients who were on a typical antipsychotic medication (SZ1) and 5 patients who were treated with clozapine (SZ2). Patients with a history of drug or alcohol abuse, developmental disability, significant head injury, epilepsy, or other neurological deficits were excluded. At interview, a battery of rating scales was administered including the Scale for the Assessment of Positive Symptoms (SAPS), the
Figure 2. An output screen of SCORES after a segment of skin conductance complex of two overlapping SCRs on a sloping baseline had been decomposed into its constituent parts. The raw skin conductance complex and the curve-fitted curve are superimposed (top of the panel). Note that the two traces are indistinguishable from each other. Below them are the components—a tonic SCL and further down, a residual curve left from the previous response, and two decomposed SCRs. The values of the four SCR model parameters of the “pure” SCR 1 have been obtained and are now ready for various measurements. Note that the time difference between the two targets (T) is the same as the onset time difference between SCR 1 and SCR 2. Scale for the Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale (PANSS), the Montgomery Asberg Depression Rating Scale (MADRS), and the core depression rating scale (Parker et al 1990). Normal control (NC) subjects (mean age 5 45.4, SD 5 15.0 years) were volunteers from the community who had no history of psychiatric illness and no history of drug or alcohol abuse, developmental disability, significant head injury, epilepsy, or other neurological deficits.
Data Acquisition Skin conductance (SC) was recorded via a pair of silver–silver chloride electrodes, approximately 0.8 cm2 in contact area, filled with electrode paste (0.05 mol/L NaCl in an inert viscous ointment base) placed on the volar surface of the distal phalanges of digits II and III of the nondominant hand after the skin area was wiped with an alcohol swab. The electrode pairs forming part of the input circuit were excited by a constant voltage of 0.5 V (Lykken and Venables 1971; Fowles et al 1981). The current
Electrodermal Activity in Schizophrenia
change representing conductance was recorded using a direct current amplifier and digitized at 250 Hz to a range of 16 bits. The system resolution was 0.00085 mS/bit, and noise level was of the same order. SCORES detected any skin conductance signal with a signal-to-noise ratio of 5. The reliable working lower limit of the current system is estimated to be 0.005 mS, which is an order of magnitude larger than the conventional lower limit of 0.05 mS, a constraint due to the older chart recording systems. The subjects were seated comfortably in a quiet, dimly lit laboratory with ambient air regulated a preset temperature at 24 6 1°C. Subjects sat facing a monitor screen and wearing a pair of headphones with the operator in an adjacent room. A conventional auditory oddball paradigm was employed, with a constant ISI of 1.32 sec. Auditory stimulation consisted of tones at 80 dB SPL lasting 50 msec having a rise and a fall time of 10 msec, with a frequency of 1000 Hz for backgrounds and 1500 Hz for targets (15%). A total of 40 target tones was presented in a randomized fixed sequence with intertarget intervals (ITIs) varying between 2.64 and 15.84 sec. Subjects were instructed to attend to the target tone and respond with a button press “as quickly as possible.” They were asked to fixate on a colored dot on the video screen. Skin conductance, full head electroencephalogram, and electro-oculogram were recorded simultaneously and continuously for 6.5 min. Only the SC data are reported in this study.
SCR and Skin Conductance Level (SCL) Measurement Each 10-sec epoch following a stimulus was inspected by an experimenter, and any SCR within 1–3 sec following each of the 40 targets in each subject was then fully evaluated using SCORES. The segments containing composite SC signals were decomposed into phasic and tonic components. The initial SC value at stimulus onset (a0), the SCL, and the four SCR-model parameter values— onset time (Tos1), gain (g1), rise time (tr), and decay time constant (td)—were obtained. The four SCR parameters that define the waveform of the phasic “pure” SCR using a sigmoid-exponential mathematical function (Equation SCR, Appendix, Lim et al 1997) are reproduced here:
fs1 5 0, for t # Tos; and fs1 5 g1 exp[2(t 2 Tos1)/td]/[1 1 ((t 2 Tos1)/tr)22]2, for t . Tos, where t 5 any instant in seconds following a stimulus, an independent variable; and the four parameters are: g1 5 gain; Tos1 5 response onset time; tr 5 rise time; and td 5 decay time constant. It is worth pointing out that gain (g1) is a mathematical concept, and it is not clear at this stage if it reflects central neuronal amplification. The SCR parameter values of each response provided six SCR variables: SCR peak amplitude (SCR amp), peak latency (SCR lat), area under curve (SCR area), recovery half time (SCR rec.t/2), recovery time constant (SCR rec.tc), and maximum rise slope (max.SCR ris.s). Although SCR area has been considered a more stable measure of EDA activity than SCR amplitude (Traxel 1957 cited by Boucsein 1992), it has not been used in the clinical psychophysiological literature
BIOL PSYCHIATRY 1999;45:127–135
129
(Bouscein 1992, p 147). The maximum rise slope (max.SCR ris.s) has also not been previously employed. The intrasubject mean and median scores of each SCR variable were determined. The mean of the median scores of the patient group was expressed as a percentage of the corresponding value in the normal controls. The number of SCRs was also obtained in the three groups (SZ, SZ1, and NC) using two amplitude inclusion criteria: one at the conventional threshold level of 0.05 mS (HT) and another at a lower level of 0.005 mS (LT). The missing values (because of absence of response) did not contribute to the means. Researchers who are interested in using this software package (SCORES) are invited to contact the first author.
Analysis The variables examined included response prevalence (number of responders as a percentage of number of subjects tested), response rate (number of SCRs as a percentage of number of targets), mean and standard deviation of medians of the SCR model parameters (Tos1, g1, tr, td), and other SCR variables (a0, SCL, SCR amp, SCR lat, SCR rec.t/2, SCR rec.tc, SCR area, and max.SCR ris.s). The numbers of SCRs for the three groups (NC, SZ, SZ1) were compared using the Wilcoxon rank sum test. The SCR variables of two data sets (LT and HT) of the NC and the SZ1 group were examined. The skin conductance variables (Tos1, a0, g1, tr, td, SCL, SCR amp, SCR lat, SCR rec.t/2, SCR rec.tc, SCR area, and max.SCR ris.s) were submitted separately to one-way analyses of variance (ANOVAs) covaried with age over the factor of group (SZ1, NC). To avoid the spurious influence of outliers and to satisfy the normal distribution requirements of parametric statistical tests, the outliers were removed. Outliers were defined as values greater than (less than) one and a half times the interquartile range from the upper quartile (lower quartile). Missing values were replaced by predicted values using linear regression equations for the normal (NC) and patient group (SZ1) separately. The sum of the median scores of the normal control responders, divided by the number of normal control responders, gave the NC mean score of the median (nc), and the corresponding SZ1 mean score of the median (sz) was similarly obtained. The nonresponders did not therefore contribute to the mean. The percentage change of each score from the controls was determined by (sz2nc)/nc 3 100%. To assess the differences between the SCRs above and below the conventional cutoff limit of 0.05 mS and to allow comparison with past reports, we sorted the SCR data into four groups (NC low amplitude, NC high amplitude, SZ1 low amplitude, and SZ1 high amplitude). The low-amplitude category (NC low, SZ1 low) included SCRs larger than 0.005 up to 0.05 mS, and the high-amplitude category (NC high, SZ1 high) included SCRs equal to or greater than 0.05 mS, and the high-amplitude category (NC high, SZ1 high) included SCRs equal to or greater than 0.05 mS. Before analysis, outliers were removed (for LT data, 1.1% for NC and 5.5% for SZ1 and for HT data, 4.4% for NC and 6.5% for SZ1), and group means were inserted for the replaced values. Each SCR variable was submitted separately to a oneway ANOVA with factor group (NC high and low, SZ1 high and low). Four planned post hoc comparison were performed (NC
130
C.L. Lim et al
BIOL PSYCHIATRY 1999;45:127–135
Table 1. Response Prevalence and Response Rate of Highand Low-Amplitude Threshold Data in the Control and the Schizophrenic Groups HTa NC Response rate (%) Response prevalence (%)
63 98
LTb
SZ
SZ1
c
c
36 87
43 100
NC
SZ
SZ1
71 100
c
54c 100
46 97
High-amplitude threshold SCR data: SCR amp $ 0.05 mS. Low-amplitude threshold SCR data: SCR amp $ 0.005 mS. c p value , .005. a b
high vs. low, SZ1 high vs. low, high NC vs. SZ1, and low NC vs. SZ1) if the group effect was found significant. To assess possible systematic temporal characteristics of SCR across the trials, the SCR mean amplitudes (zero values not included and hence not magnitude) associated with each target (i.e., first, second, . . . 40th target) were averaged across subjects in each group (NC and SZ1) and compared using paired t tests (paired according to target temporal positions). The temporal trend of the mean response amplitudes and the residuals of each group were also examined. Since the 5 patients treated with clozapine formed such a small subgroup (SZ2), only a limited analysis was performed by comparing this group with SZ1 (25 non– clozapine-treated patients) using a nonparametric Mann–Whitney rank sum test.
Results A total of 434 SCRs greater than or equal to 0.05 mS (HT) was obtained from 26 of 30 patients with schizophrenia (SZ), 432 SCRs from all 25 patients not treated with clozapine (SZ1), and 1269 from 49/50 normal controls (NC). Compared with the NC group, SCR numbers of the SZ and the SZ1 groups were significantly smaller (Wilcoxon rank sum test: p , .003 and p , .0002). A total of 554 SCRs greater than or equal to 0.005 mS (LT) was obtained from 29 of the 30 subjects in the SZ group and 535 from all 25 subjects in the SZ1 group, and these were significantly smaller than 1421 SCRs obtained from all 50 normal controls (Wilcoxon rank sum test: p , .004 and p , .0002). The response prevalence and the response rate of the normal control and the two patient groups for both HT and LT data sets are shown in Table 1. The response rates of both schizophrenia groups (SZ, SZ1) for either LT or HT data set were smaller than the control group. Only a small percentage of subjects tested were nonresponders, especially when the SCR amplitude inclusion criterion was extended to 0.005 mS. The group (NC, SZ1) effect was also present in the SCR median data for tr (F 5 16.22; df 5 1,72; p 5 .001), SCR lat (F 5 6.10.49; df 5 1,72; p 5 .015), and SCR rise time (SCR ris.t) (F 5 8.23; df 5 1,72; p 5 .005). These time-related SCR variables were smaller in the schizophrenic group (SZ1) than the control group (NC). In
addition, the group effects for SCR half recovery time (SCR rec.t/2), SCR 63% recovery time (SCR rec.tc), and SCR amplitude (SCR amp) tended toward the level of significance with p values of p , .07, p , .08, and p , .14, respectively. In each case the variables were smaller in the SZ1 than NC group. The mean and standard deviation of each SCR parameter (Tos1, g1, tr, td) and their percentage changes from the controls are shown in Table 2 for the low- and the high-amplitude threshold data. The corresponding results of the other SCR variables SCL, SCR amp, SCR lat, SCR rec.t/2, SCR rec.tc, SCR area, and max.SCR ris.s, including their percentage changes from the controls, are shown in Table 3. There were 11% and 22% of SCRs falling below the conventional cutoff level of 0.05 mS in the NC and the SZ1 group, respectively. The SCR variable means and standard deviations of the four subgroups are outlined in Table 4. The directions of change between low and high amplitudes were expected and reflected by the increases of amplitude-related variables (g1, SCR amp, SCR area) from low to high value in each subject group. Response onset time (Tos1) and SCL did not exhibit any group effect. The SCR variables, including g1, tr, td, a0, SCR amp, SCR lat, SCR rec.t/2, SCR rec.tc, SCR area, and max.SCR ris.s, exhibited group effects. The results of the four planned post hoc comparisons (NC high vs. low, SZ1 high vs. low, high NC vs. SZ1, and low NC vs. SZ1) for these variables are listed in Table 5. As expect, amplitude-related variables (g1, SCR amp, SCR area) showed a systematic size effect in each subject group (p , .0005). Time-related variables—rise time (tr), SCR lat, and SCR ris.t—were independent of SCR size in either subject group. Decay time constant (td) was significantly briefer in larger SCRs than in the smaller ones. This was mirrored in two other related measures, SCR rec.t/2 and SCR rec.tc, in the NC group but not in the schizophrenia group. Maximum SCR rise slope (max.SCR ris.s) of either subject group was Table 2. Profile of the Skin Conductance Model Parameters of Low (0.005 mS) and High (0.05 mS) Amplitude Thresholds in the Patients with Schizophrenia (SZ1, n 5 25) and Normal Controls (NC, n 5 50)
Mean
(SD)
Mean
(SD)
% change [(sz 2 nc)/nc] 3 100%
1.72 1.72 0.87 0.96 1.27 1.28 2.74 2.76
(0.23) (0.23) (0.70) (0.67) (0.45) (0.47) (1.28) (1.48)
1.72 1.69 0.50 0.63 0.87 0.92 2.47 2.31
(0.17) (0.20) (0.31) (0.28) (0.13) (0.12) (0.69) (0.67)
0.0 21.7 242.5a 234.4a 231.5a 228.1a 29.9 216.3
Controls SC model parameters Response onset time, Tos1 (sec) Gain, g1 Rise time, tr (sec) Decay time constant, td (sec) p , .05.
a
Schizophrenics
Electrodermal Activity in Schizophrenia
BIOL PSYCHIATRY 1999;45:127–135
Table 3. Skin Conductance Response (SCR) Variables of Low (0.005 mS) and High (0.05 mS) Amplitude Thresholds in the Patients with Schizophrenia (SZ1, n 5 25) and Normal Controls (NC, n 5 50)
SC variables
Mean
(SD)
Mean
(SD)
% change [(sz 2 nc)/nc] 3100
SCL (mS)
4.47 4.54 0.17 0.19 4.22 4.21 2.94 3.09 3.85 4.05 2.47 2.49 0.04 0.04 0.16 0.18
(2.74) (2.71) (0.12) (0.11) (1.14) (1.09) (1.25) (1.58) (1.65) (2.11) (0.95) (0.97) (0.03) (0.02) (0.13) (0.13)
4.88 4.94 0.13 0.16 3.55 3.53 2.57 2.44 3.38 3.20 1.91 1.81 0.03 0.04 0.15 0.17
(2.16) (2.15) (0.08) (0.07) (0.39) (0.39) (0.63) (0.56) (0.84) (0.76) (0.41) (0.25) (0.02) (0.02) (0.09) (0.07)
19.2 18.8 223.5 215.8 215.9a 216.2a 212.6 221.0 212.0 221.0 222.7a 227.3a 225.0 0.0 26.3 25.6
Controls
SCR amp (mS) SCR peak latency (sec) SCR rec.t/2 (sec) SCR rec.tc (sec) SCR ris.t (sec) SCR area (mS z sec) max.SCR ris.s (mS/sec)
Schizophrenics
p , .05.
a
significantly greater in the high SCR amplitude group than and the low SCR amplitude group. Time-related SCR variables (tr, SCR lat, and SCR ris.t), which were independent of SCR size, were significantly briefer in the SZ1 group than the NC for both low- and high-amplitude SCR data sets; however, gain (g1) in schizophrenia (SZ1) was smaller than in the control group in the high-amplitude SCRs, but not in the low-amplitude SCRs. The overall effects of various SCR parameter values in the low-amplitude threshold data of the three groups (NC, SZ, SZ1) are illustrated in their SCR waveforms (Figure 3). The peak amplitude and the peak latency and the rise time of the two patient groups (SZ, SZ1) were appreciably smaller than the control group. The waveforms of the two patient groups were similar, but with a slightly higher amplitude and faster recovery in the group without clozapine medication. When the SCR mean amplitudes associated with the targets were examined across the trial, they showed similar decay exponential trends with time constants of 58, 57, and 55 sec for NC, SZ, and SZ1, from their similar initial values of 0.26, 0.25, and 0.27 mS, to their respective asymptotes (steady-state levels) at 0.21, 0.13, and 0.13 mS. The target data, their decrement trends, and residual patterns of NC and SZ1 are shown in Figure 4, and their exponential decay trends together with their difference are shown in Figure 5. SCR variables a0, SCL, SCR amp, SCR area, and max.SCR ris.s in the clozapine-treated patient group were
131
significantly smaller than those in the non– clozapinetreated group (Mann–Whitney nonparametric test, p , .01).
Discussion The focus of this study was the examination of SCR in a short ISI paradigm, using a new method to score overlapping responses. The key findings in this study show: 1) electrodermal hyporesponsivity in patients with schizophrenia compared with normal controls; 2) similar SCR amplitude decrement over trial in both groups, but a lower steady-state level in the schizophrenic group; 3) briefer time-related skin conductance measures in the schizophrenics; 4) accentuated hyporeactivity in the clozapinetreated patient group compared with patients treated with typical antipsychotic medication; and 5) slower SCR incline and decline in low-amplitude SCRs than in highamplitude SCRs. Electrodermal hyporesponsivity was evident in the two schizophrenia groups (SZ and SZ1), who had twice as large a percentage of SCRs below 0.05 mS than the control group did, and their response rates varied between 57 and 76% of the normals. Both the EDA response prevalence Table 4. Mean and SD of Each SCR Variable of the Two Data Sets (lowa, highb) for Normal Controls (NC) and Patients with Schizophrenia without Clozapine (SZ1) SC variables
NC high
NC low
SZ1 high
SZ1 low
Response onset time, Tos1 (sec) Gain, g1
1.72 (0.23) 0.959 (0.676) 1.28 (0.47) 2.76 (1.50) 0.055 (0.037) 4.537 (2.742) 0.187 (0.111) 4.21 (1.10) 3.09 (1.60) 4.05 (2.13) 2.49 (0.98) 0.0438 (0.0243) 0.176 (0.129)
1.86 (0.31) 0.099 (0.045) 1.19 (0.47) 4.99 (3.11) 0.050 (0.042) 3.294 (1.776) 0.036 (0.007) 4.74 (1.33) 4.72 (2.51) 6.30 (3.44) 2.73 (1.02) 0.0087 (0.0023) 0.029 (0.012)
1.69 (0.20) 0.634 (0.277) 0.92 (0.12) 2.31 (0.67) 0.040 (0.026) 4.939 (2.150) 0.165 (0.071) 3.53 (0.39) 2.44 (0.56) 3.20 (0.76) 1.81 (0.25) 0.0419 (0.0175) 0.169 (0.074)
1.77 (0.26) 0.064 (0.018) 0.70 (0.20) 4.32 (2.80) 0.102 (0.092) 4.73 (1.65) 0.031 (0.010) 3.73 (0.48) 3.58 (1.54) 4.81 (2.17) 2.03 (0.51) 0.0084 (0.0028) 0.035 (0.017)
Rise time, tr (sec) Decay time constant, td (sec) a0 (mS) SCL (mS) SCR amp (mS) SCR peak latency (sec) SCR rec.t/2 (sec) SCR rec.tc (sec) SCR ris.t (sec) SCR area (mS z sec) max.SCR ris.s (mS/sec)
Low: 0.005 mS # SCR amp , 0.05 mS. High: SCR amp $ 0.05 mS.
a b
132
C.L. Lim et al
BIOL PSYCHIATRY 1999;45:127–135
Table 5. Statistical Significance Probability Levels of Unpaired Group t Tests Comparison of Each SCR Variable between High- and Low-Amplitude SCRs within Each Subject Group and Between Groups (NC, SZ1) for Each SCR Amplitude Category (low,a highb) SC variables Gain, g1 Rise time, tr (sec) Decay time constant, td (sec) a0 (mS) SCR amp (mS) SCR peak latency (sec) SCR rec.t/2 (sec) SCR rec.tc (sec) SCR ris.t (sec) SCR area (mS z sec) max. SCR ris.s (mS/sec)
NC (high vs. low)
SZ1 (high vs. low)
High (NC vs. SZ1)
Low (NC vs. SZ1)
0.000c 0.811 0.000c 0.946 0.000c 0.134 0.001c 0.001c 0.638 0.000c 0.000c
0.000c 0.307 0.023d 0.001c 0.000c 0.924 0.185 0.162 0.841 0.000c 0.000c
0.029d 0.004c 0.874 0.653 0.710 0.056 0.523 0.567 0.012d 0.976 0.988
0.993 0.000c 0.743 0.003c 0.996 0.004c 0.137 0.164 0.025d 1.000 0.996
Low: 0.005 mS # SCR amp , 0.05 mS. high: SCR amp $ 0.05 mS. c p , .005. d p , .05. a b
and response rate (with a conventional amplitude threshold of 0.05 mS) were higher in this study than in past studies using nonsignal stimuli with long ISIs (see Bernstein et al 1982 for review). The greater responsiveness may be at least in part due to a greater active participation by the subjects in this attend condition paradigm. Increased processing demands have been shown to increase ¨ hman 1981). The normal reelectrodermal reactivity (O
Figure 3. In comparison with the normal controls (NC), the SCR waveforms of the two schizophrenic groups (SZ and SZ1) exhibit smaller SCR amplitudes, shorter peak latencies, and faster rise times. The waveform differences between the two schizophrenic groups are marginal. Note that although the measurement window was 10 sec, the grand average SCRs may be reconstructed for any window length (15 sec in this case) using the four parameter values obtained previously for the three groups (lowamplitude threshold of 0.005 mS).
sponse rate (to targets) of 63% was almost identical to 68% (25.1/37) found in a study using a long ISI response time paradigm (Roth et al 1991), suggesting that ISI did not affect response rate in normals. The response rate in the medicated patients with schizophrenia in this study was twice as large as in that study (19% or 7.2/37). This difference is unlikely to be due to a response recovery effect (a consequence of short ISI stimulation), since such an effect would have resulted in a lower response rate in our study. The lower SCR amplitude limit of 0.005 mS increased the response rate and response prevalence to the same extent in both the patient (SZ1) and control groups, compared with the conventional high cutoff limit of 0.05 mS. This suggests that the combined use of a short ISI paradigm and the new scoring method is a viable approach to study EDA of schizophrenia and facilitate concurrent central–autonomic nervous system studies. A further advantage is that with fewer missing values, parametric statistical analysis and between-group comparisons will be more reliable. The reduced SCR amplitude of the patient group is evident in the SCR waveforms in Figure 3 and cannot be attributed to a lower arousal, since there was no group difference in the tonic SCL. The results are consistent with findings of EDA hyporeactivity in schizophrenia in multinational studies (Bernstein et al 1982) and other recent studies (Roth et al 1991; Bernstein et al 1995) using long ISI paradigms. Although g1, SCR amp, and SCR area are all amplitude-related, g1 (gain) seems to be more useful in showing hyporeactivity in schizophrenia, since it was significantly smaller than in the control group, in the high-amplitude data, whereas the other two related variables did not show any difference.
Electrodermal Activity in Schizophrenia
BIOL PSYCHIATRY 1999;45:127–135
133
Figure 5. The exponential decay trends (shown in Figure 4) and the difference of the SCRs of the normal and the schizophrenic group. Note that the curves were similar in form, but the schizophrenic (SZ1) trend was displaced downward by a constant level across the trial. Figure 4. Top panels: the SCR amplitudes (open circles) and their exponential trends (solid lines) with the time of target presentations during the test period for the NC (left) and SZ1 (right) groups. Bottom panel: their residuals after the raw data had been fitted to the exponential decay trends. The residual patterns varied about the zero line and did not exhibit any other systematic trends.
The entire SCR response ensemble of the SZ1 group was displaced downward by a constant level of 62% compared with the control group (Figure 4). The residual scores (after the trend was accounted for) provide further confidence that the trends were consistent. This finding extends measures of electrodermal hyporeactivity in schizophrenia that have been commonly reported. The exponential response decrement pattern of SCR over trial is reminiscent of a pattern of habituation; however, in this study, response decrement rates in the two groups were equally rapid, with decay time constants of just under 1 min. The fast time course shown in this study would have been difficult to uncover in paradigms with long ISI. Previous nonsignal condition studies have reported that patients with schizophrenia habituate faster than normal subjects (Bernstein et al 1982). This suggests that at least two different processes may be involved in short ISI and habituation paradigms. Time-related variables such as the SCR model parameter rise time (tr), SCR latency (SCR lat), and SCR rise time (SCR ris.t) were shorter in the schizophrenic group
(SZ1) compared with controls (Tables 2, 3). Two pieces of evidence indicate that these differences are not due to SCR size effect per se. These SCR variables did not exhibit differences between low- and high-amplitude SCRs in either control or the patient groups (Tables 4 and 5) but exhibit unambiguous definite differences between the control and the patient groups, in both the low- and high-amplitude data. Smaller SCRs are expected to rise to their peak earlier than large ones if there is an inherent mechanical relationship between size and peak latency. Contrary to this prediction, the smaller SCRs were associated with longer rise time and longer latency (Tables 4 and 5). These findings were consistent with those of Zahn et al (1981), who suggested that the faster rise time was not a direct consequence of smaller response amplitude. These time-related differences between small, and large SCRs suggest that their underlying generation processes differ. The temporal pattern of neuronal outflow may play a role here. A more dispersed or less synchronous efferent outflow may cause the end-organ activity to reach its peak later. The SCR recovery measures (SCR rec.t/2 and SCR rec.tc) were smaller in both the control and patient groups than those obtained using nonsignal long ISI paradigms (Edelberg 1970; Lockhart 1972; Venables and Christie 1980). Methodological differences may have contributed to this discrepancy. For example, SCR rec.t/2 of 5.57 sec in a rest condition was shortened by 40% to 3.34 sec in a
134
C.L. Lim et al
BIOL PSYCHIATRY 1999;45:127–135
simple task condition obtained in the same 12 subjects (derived from Table 2 of Edelberg 1970). It is interesting that while the recovery phase of smaller SCRs was slower than the larger ones, as indicated by the three related measures (td, SCR rec.t/2, and SCR rec.tc) in our normal control group, only the decay time constant (td) in the patient group showed this effect. This suggests that with respect to the SCR parameter, the decay time constant is a more robust index of SCR recovery than the other two indices. There was no difference between the patient and control groups in the recovery phase. Low-amplitude SCRs exhibit a similar SCR timing abnormality as the high-amplitude SCRs. The finding is surprising given the fact that the large SCRs outnumbered the low-amplitude SCRs by a factor of 4, suggesting a higher sensitivity of low-amplitude SCRs and that it may be imprudent to ignore the low-amplitude SCRs. A further advantage is that with fewer missing values, parametric statistical analysis and between-group comparisons become more reliable. No difference in response onset time between the groups suggests that the electrodermal hyporeactivity is unlikely to be due to a sympathetic nerve conduction defect. It is not known whether the sweat gland has actually been compromised in medicated patients with schizophrenia. Antipsychotic medication has been thought to suppress SCL more than other EDA measures (Schnur 1990). Roth et al (1991), on the basis of a study of medicated and unmedicated patients with schizophrenia, argued that electrodermal hyporeactivity in medicated patients with schizophrenia was due to anticholinergic medication. Zahn and Pickar (1993) reported differential effects between typical and atypical antipsychotic medication on electrodermal activity. The extent of medication effects on EDA would be best determined in a longitudinal study, assessing the same patients before and after treatment. There are 5.7 times as many nontarget data segments as target segments in our data, and a separate study of responses to nonsignal is in progress. The response profiles associated with nontarget and their differences from those associated with targets may shed light on attentional deficits in schizophrenia, which are generally accepted (Hazlett et al 1997). It would be interesting to compare the short ISI nonsignal results with numerous studies employing long ISI paradigms (Iacono et al 1993). The observed electrodermal hyporeactivity in the patients with schizophrenia in this series may be explained on the basis of either a central dysfunction or a reduced responsiveness of the effector end-organ or both. Central abnormalities in schizophrenia, such as cortical atrophy, hypometabolism, and cortical neurotransmitter dysfunction, have been reported (Weinberger 1988; Hazlett et al
1993; Carlsson and Carlsson 1990). These dysfunctions should be further explored with concurrent central (electroencephalography, event-related potential, functional magnetic resonance imaging, and positron-emission tomography) and EDA studies.
References Bernstein AS, Frith CD, Gruzelier JH, Patterson T, Straube E, Venables PH, et al (1982): An analysis of the skin conductance orienting response in samples of American, British, and German schizophrenics. Biol Psychol 14:155–211. Bernstein AS, Schnur DB, Bernstein P, Yeager A, Wrable J, Smith S (1995): Differing patterns of electrodermal and finger pulse responsivity in schizophrenia and depression. Psychol Med 25:51– 62. Bloch V (1993): On the centennial of the discovery of electrodermal activity. In: Roy J-C, Boucsein W, Fowles D, Gruzelier J, editors. Progress in Electrodermal Research. New York: Plenum Press, pp 1–5. Boucsein W (1992): Electrodermal Activity. New York: Plenum Press. Carlsson M, Carlsson A: (1990): Interactions between glutamatergic and monoaminergic systems within the basal ganglia— Implications for schizophrenia and Parkinson’s disease. Trends Neurosci 13:272–276. Darrow CW (1927): Sensory, secretory and electrical changes in the skin following bodily excitation. J Exp Psychol 10:197– 226. Edelberg R (1970): The information content of the recovery limb of the electrodermal response. Psychophysiology 6:527–539. Fowles DC, Christie MJ, Edelberg R, Gringes WW, Lykken DT, Venables PH (1981): Publication recommendations for electrodermal measurements. Psychophysiology 18:232–239. Hazlett EA, Dawson ME, Buchsbaum MS, Nuechterlein KH (1993): Reduced regional brain glucose metabolism assessed by positron emission tomography in electrodermal nonresponder schizophrenics: A pilot study. J Abnorm Psychol 102:39 – 46. Hazlett EA, Dawson ME, Filion DL, Schell AM (1997): Autonomic orienting and the allocation of processing resources in schizophrenia patients and putatively at-risk individuals. J Abnorm Psychol 106:171–181. Iacono WG, Lykken DT (1979): The orienting response: Importance of instructions. Schizophr Bull 5:11–14. Iacono WG, Ficken JW, Beiser M (1993): Electrodermal nonresponding in first-episode psychosis as a function of stimulus significance. In Roy J-C, Boucsein W, Fowles D, Gruzelier J, editors. Progress in Electrodermal Research. New York: Plenum Press, pp 239 –255. Kimble DP, Bagshaw MH, Pribram KH (1965): The GSR of monkeys during orienting and habituation after selective ablations of cingulate and frontal cortex. Neuropsychologia 3:121–128. Lim CL, Rennie C, Barry RJ, Bahramali H, Lazzaro I, Manor B, et al (1997): Decomposing skin conductance into tonic and phasic components. Int J Psychophysiol 25:97–107.
Electrodermal Activity in Schizophrenia
Lockhart RA (1972): Interrelationship between amplitude, latency, rise time, and Edelberg recovery measure of the galvanic skin response. Psychophysiology 9:437– 442. Lykken DT, Venables PH (1971): Direct measurement of skin conductance: A proposal for standardisation. Psychophysiology 8:656 – 672. ¨ hman A (1981): Electrodermal activity and vulnerability to O schizophrenia: A review. Biol Psychol 12:87–145. Parker G, Hadzi-Pavlovic D, Boyce P, Wilhelm K, Brodaty H, Mitchell P, Hicke I, Eyers K (1990): Classifying depression by mental state signs. Brit J Psychiat 157:55– 65. Pribram KH, McGuinness D (1975): Arousal activation and effort in the control of attention. Psychol Rev 82:116 –149. Pritchard WS (1986): Cognitive event-related potential correlates of schizophrenia. Psychol Bull 100:43– 66. Roth WT, Goodale J, Pfefferbaum A (1991): Auditory eventrelated potentials and electrodermal activity in medicated and unmedicated schizophrenics. Biol Psychiatry 29:585–599. Roy J-C, Sequeira H, Delerm B (1993): Cortical and hypothalamo-limbic control of electrodermal responses. In Roy J-C, Boucsein W, Fowles D, Gruzelier J, editors. Progress in Electrodermal Research. New York: Plenum Press, pp 73–92. Sequeira H, Roy J-C (1993): Neural control of electrodermal activity: Spinal and reticular mechanisms. In: Roy J-C, Boucsein W, Fowles D, Gruzelier J, editors. Progress in
BIOL PSYCHIATRY 1999;45:127–135
135
Electrodermal Research. New York: Plenum Press, pp 93– 114. Venables PH (1991): Autonomic activity. In: Zappulla RA, LeFever FF, Jaeger J, Bilder R, editors. Windows on the Brain. New York: New York Academy of Science, pp 191–207. Venables PH (1993): Electrodermal indices as markers for the development of schizophrenia. In: Roy J-C, Boucsein W, Fowles D, Gruzelier J, editors. Progress in Electrodermal Research. New York: Plenum Press, pp 187–205. Venables PH, Christie MJ (1980): Electrodermal activity. In: Martin I, Venables PH, editors. Techniques in Psychophysiology New York: Wiley, pp 3– 67. Wang GH (1964): The Neural Control of Sweating. Madison, WI: University of Wisconsin Press. Wang GH, Lu TW (1930): Galvanic skin reflex induced in the act by stimulation of the motor area of the cerebral cortex. Chin J Physiol 4:303–326. Weinberger DR (1988): Schizophrenia and the frontal lobe. Trends Neurosci 11:367–370. Zahn TP, Pickar D (1993): Autonomic effects of clozapine in schizophrenia: Comparison with placebo and fluphrenazine. Biol Psychiatry 34:3–12. Zahn TP, Carpenter WT, McGlashan TH (1981): Autonomic nervous system activity in acute schizophrenia: I. Method and comparison with normal controls. Arch Gen Psychiatry 38: 251–258.
Introduction
D
iscovery of electrodermal activity (EDA) in humans by Fe´re´ in 1888 (Bloch 1993) and subsequent experiments in cats (Darrow 1927; Wang and Lu 1930; Wang
From the Department of Neurology (CLL) and Cognitive Neuroscience Unit, Department of Psychiatry (EG, HB, WML, BM, CR), University of Sydney and Westmead Hospital, Sydney, Australia; and Department of Psychiatry, Nepean General Hospital, Penrith, Australia (AH). Address reprint requests to Chong Lee Lim, Neurology Department, Westmead Hospital, Westmead 2145, Australia. Received January 7, 1997; revised July 11, 1997; revised January 26, 1998; accepted February 3, 1998.
© 1999 Society of Biological Psychiatry
1964) and monkeys (Kimble et al 1965) elucidated some of the central networks underlying electrodermal activity (Roy et al 1993; Sequeira and Roy 1993). This basic research fueled numerous psychophysiological studies; a large number of these studies have focused on schizophrenia. EDA findings in schizophrenia include hyporeactivity (a higher incidence of about 40% nonresponders compared with 5–10% of normals), and faster habituation and recovery. More recent reviews highlight slow habituation and short recovery time in patients with schizophrenia, while noting some conflicting results (Boucsein 1992, pp 244 –248; Venables 1993). The lack of consistent findings in schizophrenia has been exacerbated by the heterogeneity of the disorder and differences in the paradigms employed. A small change in task instruction (Iacono and Lykken 1979), stimulus pa¨ hman 1981), and significance (Bernstein et al rameters (O 1982) can alter the proportion of nonresponders. Many previous studies used nontask paradigms with long interstimulus intervals (ISIs). Paradigms requiring attention and performance, on the other hand, may result in a higher proportion of responders and responses to stimuli. The conventional event-related potential (ERP) paradigms using short ISI stimuli have been extensively used to explore possible dysfunctions in information processing in schizophrenia (for review see Pritchard 1986). Successful use of such conventional ERP paradigms in an electrodermal study might elicit a larger proportion of responders and would also facilitate future concurrent study of central and autonomic activity. In this study, we applied a new method to score overlapping skin conductance responses (SCRs), to the study of task-relevant target SCRs in a conventional auditory oddball paradigm with short ISIs. Abundant SCR responses were obtained using this paradigm, and they frequently overlapped (Figure 1), presenting a difficult measurement task. We have recently developed a fourparameter sigmoid-exponential SCR model (Lim et al 1997), which employs a curve-fitting method to decompose response overlaps into their constituent parts. The software implementation of the method is known as SCORES (Skin Conductance Response Evaluation Sys0006-3223/99/$19.00 PII S0006-3223(98)00056-0
128
C.L. Lim et al
BIOL PSYCHIATRY 1999;45:127–135
Figure 1. Skin conductance traces during the test period of a normal subject (top panel) and a patient with schizophrenia (bottom panel). These traces were complex, consisting of numerous responses to target tones that considerably overlapped.
tem), and a brief description of how it works is provided. SCORES scans each response complex associated with each target stimulus and iteratively optimizes the model parameters so as to minimize the mean square difference between the actual and the constructed curves. The fitted curve has been shown to be almost indistinguishable from the actual raw response complex (the top two superimposed SCR curves in Figure 2). For further details please refer to the Methods section and to the previous publication about this method (Lim et al 1997). In this exploratory study, we predicted a high proportion of responders and responses to stimuli in both groups, but diminished response amplitude and delayed latency and recovery time in the schizophrenic group compared with controls.
Methods and Materials Subjects Thirty subjects (mean age 5 35.4, SD 5 9.5 years) with schizophrenia (DSM-III-R and ICD 10) as diagnosed by a psychiatrist using the Composite International Diagnostic Interview (CIDI) were compared with 50 normal control subjects. Subjects with schizophrenia were recruited from mental health services and a schizophrenic support group. All subjects with schizophrenia were medicated. Since clozapine, the atypical antipsychotic, has been reported to have a marked attenuation effect on electrodermal activity (Zahn and Pickar 1993), the 30 patients (SZ) were separated into two groups—25 patients who were on a typical antipsychotic medication (SZ1) and 5 patients who were treated with clozapine (SZ2). Patients with a history of drug or alcohol abuse, developmental disability, significant head injury, epilepsy, or other neurological deficits were excluded. At interview, a battery of rating scales was administered including the Scale for the Assessment of Positive Symptoms (SAPS), the
Figure 2. An output screen of SCORES after a segment of skin conductance complex of two overlapping SCRs on a sloping baseline had been decomposed into its constituent parts. The raw skin conductance complex and the curve-fitted curve are superimposed (top of the panel). Note that the two traces are indistinguishable from each other. Below them are the components—a tonic SCL and further down, a residual curve left from the previous response, and two decomposed SCRs. The values of the four SCR model parameters of the “pure” SCR 1 have been obtained and are now ready for various measurements. Note that the time difference between the two targets (T) is the same as the onset time difference between SCR 1 and SCR 2. Scale for the Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale (PANSS), the Montgomery Asberg Depression Rating Scale (MADRS), and the core depression rating scale (Parker et al 1990). Normal control (NC) subjects (mean age 5 45.4, SD 5 15.0 years) were volunteers from the community who had no history of psychiatric illness and no history of drug or alcohol abuse, developmental disability, significant head injury, epilepsy, or other neurological deficits.
Data Acquisition Skin conductance (SC) was recorded via a pair of silver–silver chloride electrodes, approximately 0.8 cm2 in contact area, filled with electrode paste (0.05 mol/L NaCl in an inert viscous ointment base) placed on the volar surface of the distal phalanges of digits II and III of the nondominant hand after the skin area was wiped with an alcohol swab. The electrode pairs forming part of the input circuit were excited by a constant voltage of 0.5 V (Lykken and Venables 1971; Fowles et al 1981). The current
Electrodermal Activity in Schizophrenia
change representing conductance was recorded using a direct current amplifier and digitized at 250 Hz to a range of 16 bits. The system resolution was 0.00085 mS/bit, and noise level was of the same order. SCORES detected any skin conductance signal with a signal-to-noise ratio of 5. The reliable working lower limit of the current system is estimated to be 0.005 mS, which is an order of magnitude larger than the conventional lower limit of 0.05 mS, a constraint due to the older chart recording systems. The subjects were seated comfortably in a quiet, dimly lit laboratory with ambient air regulated a preset temperature at 24 6 1°C. Subjects sat facing a monitor screen and wearing a pair of headphones with the operator in an adjacent room. A conventional auditory oddball paradigm was employed, with a constant ISI of 1.32 sec. Auditory stimulation consisted of tones at 80 dB SPL lasting 50 msec having a rise and a fall time of 10 msec, with a frequency of 1000 Hz for backgrounds and 1500 Hz for targets (15%). A total of 40 target tones was presented in a randomized fixed sequence with intertarget intervals (ITIs) varying between 2.64 and 15.84 sec. Subjects were instructed to attend to the target tone and respond with a button press “as quickly as possible.” They were asked to fixate on a colored dot on the video screen. Skin conductance, full head electroencephalogram, and electro-oculogram were recorded simultaneously and continuously for 6.5 min. Only the SC data are reported in this study.
SCR and Skin Conductance Level (SCL) Measurement Each 10-sec epoch following a stimulus was inspected by an experimenter, and any SCR within 1–3 sec following each of the 40 targets in each subject was then fully evaluated using SCORES. The segments containing composite SC signals were decomposed into phasic and tonic components. The initial SC value at stimulus onset (a0), the SCL, and the four SCR-model parameter values— onset time (Tos1), gain (g1), rise time (tr), and decay time constant (td)—were obtained. The four SCR parameters that define the waveform of the phasic “pure” SCR using a sigmoid-exponential mathematical function (Equation SCR, Appendix, Lim et al 1997) are reproduced here:
fs1 5 0, for t # Tos; and fs1 5 g1 exp[2(t 2 Tos1)/td]/[1 1 ((t 2 Tos1)/tr)22]2, for t . Tos, where t 5 any instant in seconds following a stimulus, an independent variable; and the four parameters are: g1 5 gain; Tos1 5 response onset time; tr 5 rise time; and td 5 decay time constant. It is worth pointing out that gain (g1) is a mathematical concept, and it is not clear at this stage if it reflects central neuronal amplification. The SCR parameter values of each response provided six SCR variables: SCR peak amplitude (SCR amp), peak latency (SCR lat), area under curve (SCR area), recovery half time (SCR rec.t/2), recovery time constant (SCR rec.tc), and maximum rise slope (max.SCR ris.s). Although SCR area has been considered a more stable measure of EDA activity than SCR amplitude (Traxel 1957 cited by Boucsein 1992), it has not been used in the clinical psychophysiological literature
BIOL PSYCHIATRY 1999;45:127–135
129
(Bouscein 1992, p 147). The maximum rise slope (max.SCR ris.s) has also not been previously employed. The intrasubject mean and median scores of each SCR variable were determined. The mean of the median scores of the patient group was expressed as a percentage of the corresponding value in the normal controls. The number of SCRs was also obtained in the three groups (SZ, SZ1, and NC) using two amplitude inclusion criteria: one at the conventional threshold level of 0.05 mS (HT) and another at a lower level of 0.005 mS (LT). The missing values (because of absence of response) did not contribute to the means. Researchers who are interested in using this software package (SCORES) are invited to contact the first author.
Analysis The variables examined included response prevalence (number of responders as a percentage of number of subjects tested), response rate (number of SCRs as a percentage of number of targets), mean and standard deviation of medians of the SCR model parameters (Tos1, g1, tr, td), and other SCR variables (a0, SCL, SCR amp, SCR lat, SCR rec.t/2, SCR rec.tc, SCR area, and max.SCR ris.s). The numbers of SCRs for the three groups (NC, SZ, SZ1) were compared using the Wilcoxon rank sum test. The SCR variables of two data sets (LT and HT) of the NC and the SZ1 group were examined. The skin conductance variables (Tos1, a0, g1, tr, td, SCL, SCR amp, SCR lat, SCR rec.t/2, SCR rec.tc, SCR area, and max.SCR ris.s) were submitted separately to one-way analyses of variance (ANOVAs) covaried with age over the factor of group (SZ1, NC). To avoid the spurious influence of outliers and to satisfy the normal distribution requirements of parametric statistical tests, the outliers were removed. Outliers were defined as values greater than (less than) one and a half times the interquartile range from the upper quartile (lower quartile). Missing values were replaced by predicted values using linear regression equations for the normal (NC) and patient group (SZ1) separately. The sum of the median scores of the normal control responders, divided by the number of normal control responders, gave the NC mean score of the median (nc), and the corresponding SZ1 mean score of the median (sz) was similarly obtained. The nonresponders did not therefore contribute to the mean. The percentage change of each score from the controls was determined by (sz2nc)/nc 3 100%. To assess the differences between the SCRs above and below the conventional cutoff limit of 0.05 mS and to allow comparison with past reports, we sorted the SCR data into four groups (NC low amplitude, NC high amplitude, SZ1 low amplitude, and SZ1 high amplitude). The low-amplitude category (NC low, SZ1 low) included SCRs larger than 0.005 up to 0.05 mS, and the high-amplitude category (NC high, SZ1 high) included SCRs equal to or greater than 0.05 mS, and the high-amplitude category (NC high, SZ1 high) included SCRs equal to or greater than 0.05 mS. Before analysis, outliers were removed (for LT data, 1.1% for NC and 5.5% for SZ1 and for HT data, 4.4% for NC and 6.5% for SZ1), and group means were inserted for the replaced values. Each SCR variable was submitted separately to a oneway ANOVA with factor group (NC high and low, SZ1 high and low). Four planned post hoc comparison were performed (NC
130
C.L. Lim et al
BIOL PSYCHIATRY 1999;45:127–135
Table 1. Response Prevalence and Response Rate of Highand Low-Amplitude Threshold Data in the Control and the Schizophrenic Groups HTa NC Response rate (%) Response prevalence (%)
63 98
LTb
SZ
SZ1
c
c
36 87
43 100
NC
SZ
SZ1
71 100
c
54c 100
46 97
High-amplitude threshold SCR data: SCR amp $ 0.05 mS. Low-amplitude threshold SCR data: SCR amp $ 0.005 mS. c p value , .005. a b
high vs. low, SZ1 high vs. low, high NC vs. SZ1, and low NC vs. SZ1) if the group effect was found significant. To assess possible systematic temporal characteristics of SCR across the trials, the SCR mean amplitudes (zero values not included and hence not magnitude) associated with each target (i.e., first, second, . . . 40th target) were averaged across subjects in each group (NC and SZ1) and compared using paired t tests (paired according to target temporal positions). The temporal trend of the mean response amplitudes and the residuals of each group were also examined. Since the 5 patients treated with clozapine formed such a small subgroup (SZ2), only a limited analysis was performed by comparing this group with SZ1 (25 non– clozapine-treated patients) using a nonparametric Mann–Whitney rank sum test.
Results A total of 434 SCRs greater than or equal to 0.05 mS (HT) was obtained from 26 of 30 patients with schizophrenia (SZ), 432 SCRs from all 25 patients not treated with clozapine (SZ1), and 1269 from 49/50 normal controls (NC). Compared with the NC group, SCR numbers of the SZ and the SZ1 groups were significantly smaller (Wilcoxon rank sum test: p , .003 and p , .0002). A total of 554 SCRs greater than or equal to 0.005 mS (LT) was obtained from 29 of the 30 subjects in the SZ group and 535 from all 25 subjects in the SZ1 group, and these were significantly smaller than 1421 SCRs obtained from all 50 normal controls (Wilcoxon rank sum test: p , .004 and p , .0002). The response prevalence and the response rate of the normal control and the two patient groups for both HT and LT data sets are shown in Table 1. The response rates of both schizophrenia groups (SZ, SZ1) for either LT or HT data set were smaller than the control group. Only a small percentage of subjects tested were nonresponders, especially when the SCR amplitude inclusion criterion was extended to 0.005 mS. The group (NC, SZ1) effect was also present in the SCR median data for tr (F 5 16.22; df 5 1,72; p 5 .001), SCR lat (F 5 6.10.49; df 5 1,72; p 5 .015), and SCR rise time (SCR ris.t) (F 5 8.23; df 5 1,72; p 5 .005). These time-related SCR variables were smaller in the schizophrenic group (SZ1) than the control group (NC). In
addition, the group effects for SCR half recovery time (SCR rec.t/2), SCR 63% recovery time (SCR rec.tc), and SCR amplitude (SCR amp) tended toward the level of significance with p values of p , .07, p , .08, and p , .14, respectively. In each case the variables were smaller in the SZ1 than NC group. The mean and standard deviation of each SCR parameter (Tos1, g1, tr, td) and their percentage changes from the controls are shown in Table 2 for the low- and the high-amplitude threshold data. The corresponding results of the other SCR variables SCL, SCR amp, SCR lat, SCR rec.t/2, SCR rec.tc, SCR area, and max.SCR ris.s, including their percentage changes from the controls, are shown in Table 3. There were 11% and 22% of SCRs falling below the conventional cutoff level of 0.05 mS in the NC and the SZ1 group, respectively. The SCR variable means and standard deviations of the four subgroups are outlined in Table 4. The directions of change between low and high amplitudes were expected and reflected by the increases of amplitude-related variables (g1, SCR amp, SCR area) from low to high value in each subject group. Response onset time (Tos1) and SCL did not exhibit any group effect. The SCR variables, including g1, tr, td, a0, SCR amp, SCR lat, SCR rec.t/2, SCR rec.tc, SCR area, and max.SCR ris.s, exhibited group effects. The results of the four planned post hoc comparisons (NC high vs. low, SZ1 high vs. low, high NC vs. SZ1, and low NC vs. SZ1) for these variables are listed in Table 5. As expect, amplitude-related variables (g1, SCR amp, SCR area) showed a systematic size effect in each subject group (p , .0005). Time-related variables—rise time (tr), SCR lat, and SCR ris.t—were independent of SCR size in either subject group. Decay time constant (td) was significantly briefer in larger SCRs than in the smaller ones. This was mirrored in two other related measures, SCR rec.t/2 and SCR rec.tc, in the NC group but not in the schizophrenia group. Maximum SCR rise slope (max.SCR ris.s) of either subject group was Table 2. Profile of the Skin Conductance Model Parameters of Low (0.005 mS) and High (0.05 mS) Amplitude Thresholds in the Patients with Schizophrenia (SZ1, n 5 25) and Normal Controls (NC, n 5 50)
Mean
(SD)
Mean
(SD)
% change [(sz 2 nc)/nc] 3 100%
1.72 1.72 0.87 0.96 1.27 1.28 2.74 2.76
(0.23) (0.23) (0.70) (0.67) (0.45) (0.47) (1.28) (1.48)
1.72 1.69 0.50 0.63 0.87 0.92 2.47 2.31
(0.17) (0.20) (0.31) (0.28) (0.13) (0.12) (0.69) (0.67)
0.0 21.7 242.5a 234.4a 231.5a 228.1a 29.9 216.3
Controls SC model parameters Response onset time, Tos1 (sec) Gain, g1 Rise time, tr (sec) Decay time constant, td (sec) p , .05.
a
Schizophrenics
Electrodermal Activity in Schizophrenia
BIOL PSYCHIATRY 1999;45:127–135
Table 3. Skin Conductance Response (SCR) Variables of Low (0.005 mS) and High (0.05 mS) Amplitude Thresholds in the Patients with Schizophrenia (SZ1, n 5 25) and Normal Controls (NC, n 5 50)
SC variables
Mean
(SD)
Mean
(SD)
% change [(sz 2 nc)/nc] 3100
SCL (mS)
4.47 4.54 0.17 0.19 4.22 4.21 2.94 3.09 3.85 4.05 2.47 2.49 0.04 0.04 0.16 0.18
(2.74) (2.71) (0.12) (0.11) (1.14) (1.09) (1.25) (1.58) (1.65) (2.11) (0.95) (0.97) (0.03) (0.02) (0.13) (0.13)
4.88 4.94 0.13 0.16 3.55 3.53 2.57 2.44 3.38 3.20 1.91 1.81 0.03 0.04 0.15 0.17
(2.16) (2.15) (0.08) (0.07) (0.39) (0.39) (0.63) (0.56) (0.84) (0.76) (0.41) (0.25) (0.02) (0.02) (0.09) (0.07)
19.2 18.8 223.5 215.8 215.9a 216.2a 212.6 221.0 212.0 221.0 222.7a 227.3a 225.0 0.0 26.3 25.6
Controls
SCR amp (mS) SCR peak latency (sec) SCR rec.t/2 (sec) SCR rec.tc (sec) SCR ris.t (sec) SCR area (mS z sec) max.SCR ris.s (mS/sec)
Schizophrenics
p , .05.
a
significantly greater in the high SCR amplitude group than and the low SCR amplitude group. Time-related SCR variables (tr, SCR lat, and SCR ris.t), which were independent of SCR size, were significantly briefer in the SZ1 group than the NC for both low- and high-amplitude SCR data sets; however, gain (g1) in schizophrenia (SZ1) was smaller than in the control group in the high-amplitude SCRs, but not in the low-amplitude SCRs. The overall effects of various SCR parameter values in the low-amplitude threshold data of the three groups (NC, SZ, SZ1) are illustrated in their SCR waveforms (Figure 3). The peak amplitude and the peak latency and the rise time of the two patient groups (SZ, SZ1) were appreciably smaller than the control group. The waveforms of the two patient groups were similar, but with a slightly higher amplitude and faster recovery in the group without clozapine medication. When the SCR mean amplitudes associated with the targets were examined across the trial, they showed similar decay exponential trends with time constants of 58, 57, and 55 sec for NC, SZ, and SZ1, from their similar initial values of 0.26, 0.25, and 0.27 mS, to their respective asymptotes (steady-state levels) at 0.21, 0.13, and 0.13 mS. The target data, their decrement trends, and residual patterns of NC and SZ1 are shown in Figure 4, and their exponential decay trends together with their difference are shown in Figure 5. SCR variables a0, SCL, SCR amp, SCR area, and max.SCR ris.s in the clozapine-treated patient group were
131
significantly smaller than those in the non– clozapinetreated group (Mann–Whitney nonparametric test, p , .01).
Discussion The focus of this study was the examination of SCR in a short ISI paradigm, using a new method to score overlapping responses. The key findings in this study show: 1) electrodermal hyporesponsivity in patients with schizophrenia compared with normal controls; 2) similar SCR amplitude decrement over trial in both groups, but a lower steady-state level in the schizophrenic group; 3) briefer time-related skin conductance measures in the schizophrenics; 4) accentuated hyporeactivity in the clozapinetreated patient group compared with patients treated with typical antipsychotic medication; and 5) slower SCR incline and decline in low-amplitude SCRs than in highamplitude SCRs. Electrodermal hyporesponsivity was evident in the two schizophrenia groups (SZ and SZ1), who had twice as large a percentage of SCRs below 0.05 mS than the control group did, and their response rates varied between 57 and 76% of the normals. Both the EDA response prevalence Table 4. Mean and SD of Each SCR Variable of the Two Data Sets (lowa, highb) for Normal Controls (NC) and Patients with Schizophrenia without Clozapine (SZ1) SC variables
NC high
NC low
SZ1 high
SZ1 low
Response onset time, Tos1 (sec) Gain, g1
1.72 (0.23) 0.959 (0.676) 1.28 (0.47) 2.76 (1.50) 0.055 (0.037) 4.537 (2.742) 0.187 (0.111) 4.21 (1.10) 3.09 (1.60) 4.05 (2.13) 2.49 (0.98) 0.0438 (0.0243) 0.176 (0.129)
1.86 (0.31) 0.099 (0.045) 1.19 (0.47) 4.99 (3.11) 0.050 (0.042) 3.294 (1.776) 0.036 (0.007) 4.74 (1.33) 4.72 (2.51) 6.30 (3.44) 2.73 (1.02) 0.0087 (0.0023) 0.029 (0.012)
1.69 (0.20) 0.634 (0.277) 0.92 (0.12) 2.31 (0.67) 0.040 (0.026) 4.939 (2.150) 0.165 (0.071) 3.53 (0.39) 2.44 (0.56) 3.20 (0.76) 1.81 (0.25) 0.0419 (0.0175) 0.169 (0.074)
1.77 (0.26) 0.064 (0.018) 0.70 (0.20) 4.32 (2.80) 0.102 (0.092) 4.73 (1.65) 0.031 (0.010) 3.73 (0.48) 3.58 (1.54) 4.81 (2.17) 2.03 (0.51) 0.0084 (0.0028) 0.035 (0.017)
Rise time, tr (sec) Decay time constant, td (sec) a0 (mS) SCL (mS) SCR amp (mS) SCR peak latency (sec) SCR rec.t/2 (sec) SCR rec.tc (sec) SCR ris.t (sec) SCR area (mS z sec) max.SCR ris.s (mS/sec)
Low: 0.005 mS # SCR amp , 0.05 mS. High: SCR amp $ 0.05 mS.
a b
132
C.L. Lim et al
BIOL PSYCHIATRY 1999;45:127–135
Table 5. Statistical Significance Probability Levels of Unpaired Group t Tests Comparison of Each SCR Variable between High- and Low-Amplitude SCRs within Each Subject Group and Between Groups (NC, SZ1) for Each SCR Amplitude Category (low,a highb) SC variables Gain, g1 Rise time, tr (sec) Decay time constant, td (sec) a0 (mS) SCR amp (mS) SCR peak latency (sec) SCR rec.t/2 (sec) SCR rec.tc (sec) SCR ris.t (sec) SCR area (mS z sec) max. SCR ris.s (mS/sec)
NC (high vs. low)
SZ1 (high vs. low)
High (NC vs. SZ1)
Low (NC vs. SZ1)
0.000c 0.811 0.000c 0.946 0.000c 0.134 0.001c 0.001c 0.638 0.000c 0.000c
0.000c 0.307 0.023d 0.001c 0.000c 0.924 0.185 0.162 0.841 0.000c 0.000c
0.029d 0.004c 0.874 0.653 0.710 0.056 0.523 0.567 0.012d 0.976 0.988
0.993 0.000c 0.743 0.003c 0.996 0.004c 0.137 0.164 0.025d 1.000 0.996
Low: 0.005 mS # SCR amp , 0.05 mS. high: SCR amp $ 0.05 mS. c p , .005. d p , .05. a b
and response rate (with a conventional amplitude threshold of 0.05 mS) were higher in this study than in past studies using nonsignal stimuli with long ISIs (see Bernstein et al 1982 for review). The greater responsiveness may be at least in part due to a greater active participation by the subjects in this attend condition paradigm. Increased processing demands have been shown to increase ¨ hman 1981). The normal reelectrodermal reactivity (O
Figure 3. In comparison with the normal controls (NC), the SCR waveforms of the two schizophrenic groups (SZ and SZ1) exhibit smaller SCR amplitudes, shorter peak latencies, and faster rise times. The waveform differences between the two schizophrenic groups are marginal. Note that although the measurement window was 10 sec, the grand average SCRs may be reconstructed for any window length (15 sec in this case) using the four parameter values obtained previously for the three groups (lowamplitude threshold of 0.005 mS).
sponse rate (to targets) of 63% was almost identical to 68% (25.1/37) found in a study using a long ISI response time paradigm (Roth et al 1991), suggesting that ISI did not affect response rate in normals. The response rate in the medicated patients with schizophrenia in this study was twice as large as in that study (19% or 7.2/37). This difference is unlikely to be due to a response recovery effect (a consequence of short ISI stimulation), since such an effect would have resulted in a lower response rate in our study. The lower SCR amplitude limit of 0.005 mS increased the response rate and response prevalence to the same extent in both the patient (SZ1) and control groups, compared with the conventional high cutoff limit of 0.05 mS. This suggests that the combined use of a short ISI paradigm and the new scoring method is a viable approach to study EDA of schizophrenia and facilitate concurrent central–autonomic nervous system studies. A further advantage is that with fewer missing values, parametric statistical analysis and between-group comparisons will be more reliable. The reduced SCR amplitude of the patient group is evident in the SCR waveforms in Figure 3 and cannot be attributed to a lower arousal, since there was no group difference in the tonic SCL. The results are consistent with findings of EDA hyporeactivity in schizophrenia in multinational studies (Bernstein et al 1982) and other recent studies (Roth et al 1991; Bernstein et al 1995) using long ISI paradigms. Although g1, SCR amp, and SCR area are all amplitude-related, g1 (gain) seems to be more useful in showing hyporeactivity in schizophrenia, since it was significantly smaller than in the control group, in the high-amplitude data, whereas the other two related variables did not show any difference.
Electrodermal Activity in Schizophrenia
BIOL PSYCHIATRY 1999;45:127–135
133
Figure 5. The exponential decay trends (shown in Figure 4) and the difference of the SCRs of the normal and the schizophrenic group. Note that the curves were similar in form, but the schizophrenic (SZ1) trend was displaced downward by a constant level across the trial. Figure 4. Top panels: the SCR amplitudes (open circles) and their exponential trends (solid lines) with the time of target presentations during the test period for the NC (left) and SZ1 (right) groups. Bottom panel: their residuals after the raw data had been fitted to the exponential decay trends. The residual patterns varied about the zero line and did not exhibit any other systematic trends.
The entire SCR response ensemble of the SZ1 group was displaced downward by a constant level of 62% compared with the control group (Figure 4). The residual scores (after the trend was accounted for) provide further confidence that the trends were consistent. This finding extends measures of electrodermal hyporeactivity in schizophrenia that have been commonly reported. The exponential response decrement pattern of SCR over trial is reminiscent of a pattern of habituation; however, in this study, response decrement rates in the two groups were equally rapid, with decay time constants of just under 1 min. The fast time course shown in this study would have been difficult to uncover in paradigms with long ISI. Previous nonsignal condition studies have reported that patients with schizophrenia habituate faster than normal subjects (Bernstein et al 1982). This suggests that at least two different processes may be involved in short ISI and habituation paradigms. Time-related variables such as the SCR model parameter rise time (tr), SCR latency (SCR lat), and SCR rise time (SCR ris.t) were shorter in the schizophrenic group
(SZ1) compared with controls (Tables 2, 3). Two pieces of evidence indicate that these differences are not due to SCR size effect per se. These SCR variables did not exhibit differences between low- and high-amplitude SCRs in either control or the patient groups (Tables 4 and 5) but exhibit unambiguous definite differences between the control and the patient groups, in both the low- and high-amplitude data. Smaller SCRs are expected to rise to their peak earlier than large ones if there is an inherent mechanical relationship between size and peak latency. Contrary to this prediction, the smaller SCRs were associated with longer rise time and longer latency (Tables 4 and 5). These findings were consistent with those of Zahn et al (1981), who suggested that the faster rise time was not a direct consequence of smaller response amplitude. These time-related differences between small, and large SCRs suggest that their underlying generation processes differ. The temporal pattern of neuronal outflow may play a role here. A more dispersed or less synchronous efferent outflow may cause the end-organ activity to reach its peak later. The SCR recovery measures (SCR rec.t/2 and SCR rec.tc) were smaller in both the control and patient groups than those obtained using nonsignal long ISI paradigms (Edelberg 1970; Lockhart 1972; Venables and Christie 1980). Methodological differences may have contributed to this discrepancy. For example, SCR rec.t/2 of 5.57 sec in a rest condition was shortened by 40% to 3.34 sec in a
134
C.L. Lim et al
BIOL PSYCHIATRY 1999;45:127–135
simple task condition obtained in the same 12 subjects (derived from Table 2 of Edelberg 1970). It is interesting that while the recovery phase of smaller SCRs was slower than the larger ones, as indicated by the three related measures (td, SCR rec.t/2, and SCR rec.tc) in our normal control group, only the decay time constant (td) in the patient group showed this effect. This suggests that with respect to the SCR parameter, the decay time constant is a more robust index of SCR recovery than the other two indices. There was no difference between the patient and control groups in the recovery phase. Low-amplitude SCRs exhibit a similar SCR timing abnormality as the high-amplitude SCRs. The finding is surprising given the fact that the large SCRs outnumbered the low-amplitude SCRs by a factor of 4, suggesting a higher sensitivity of low-amplitude SCRs and that it may be imprudent to ignore the low-amplitude SCRs. A further advantage is that with fewer missing values, parametric statistical analysis and between-group comparisons become more reliable. No difference in response onset time between the groups suggests that the electrodermal hyporeactivity is unlikely to be due to a sympathetic nerve conduction defect. It is not known whether the sweat gland has actually been compromised in medicated patients with schizophrenia. Antipsychotic medication has been thought to suppress SCL more than other EDA measures (Schnur 1990). Roth et al (1991), on the basis of a study of medicated and unmedicated patients with schizophrenia, argued that electrodermal hyporeactivity in medicated patients with schizophrenia was due to anticholinergic medication. Zahn and Pickar (1993) reported differential effects between typical and atypical antipsychotic medication on electrodermal activity. The extent of medication effects on EDA would be best determined in a longitudinal study, assessing the same patients before and after treatment. There are 5.7 times as many nontarget data segments as target segments in our data, and a separate study of responses to nonsignal is in progress. The response profiles associated with nontarget and their differences from those associated with targets may shed light on attentional deficits in schizophrenia, which are generally accepted (Hazlett et al 1997). It would be interesting to compare the short ISI nonsignal results with numerous studies employing long ISI paradigms (Iacono et al 1993). The observed electrodermal hyporeactivity in the patients with schizophrenia in this series may be explained on the basis of either a central dysfunction or a reduced responsiveness of the effector end-organ or both. Central abnormalities in schizophrenia, such as cortical atrophy, hypometabolism, and cortical neurotransmitter dysfunction, have been reported (Weinberger 1988; Hazlett et al
1993; Carlsson and Carlsson 1990). These dysfunctions should be further explored with concurrent central (electroencephalography, event-related potential, functional magnetic resonance imaging, and positron-emission tomography) and EDA studies.
References Bernstein AS, Frith CD, Gruzelier JH, Patterson T, Straube E, Venables PH, et al (1982): An analysis of the skin conductance orienting response in samples of American, British, and German schizophrenics. Biol Psychol 14:155–211. Bernstein AS, Schnur DB, Bernstein P, Yeager A, Wrable J, Smith S (1995): Differing patterns of electrodermal and finger pulse responsivity in schizophrenia and depression. Psychol Med 25:51– 62. Bloch V (1993): On the centennial of the discovery of electrodermal activity. In: Roy J-C, Boucsein W, Fowles D, Gruzelier J, editors. Progress in Electrodermal Research. New York: Plenum Press, pp 1–5. Boucsein W (1992): Electrodermal Activity. New York: Plenum Press. Carlsson M, Carlsson A: (1990): Interactions between glutamatergic and monoaminergic systems within the basal ganglia— Implications for schizophrenia and Parkinson’s disease. Trends Neurosci 13:272–276. Darrow CW (1927): Sensory, secretory and electrical changes in the skin following bodily excitation. J Exp Psychol 10:197– 226. Edelberg R (1970): The information content of the recovery limb of the electrodermal response. Psychophysiology 6:527–539. Fowles DC, Christie MJ, Edelberg R, Gringes WW, Lykken DT, Venables PH (1981): Publication recommendations for electrodermal measurements. Psychophysiology 18:232–239. Hazlett EA, Dawson ME, Buchsbaum MS, Nuechterlein KH (1993): Reduced regional brain glucose metabolism assessed by positron emission tomography in electrodermal nonresponder schizophrenics: A pilot study. J Abnorm Psychol 102:39 – 46. Hazlett EA, Dawson ME, Filion DL, Schell AM (1997): Autonomic orienting and the allocation of processing resources in schizophrenia patients and putatively at-risk individuals. J Abnorm Psychol 106:171–181. Iacono WG, Lykken DT (1979): The orienting response: Importance of instructions. Schizophr Bull 5:11–14. Iacono WG, Ficken JW, Beiser M (1993): Electrodermal nonresponding in first-episode psychosis as a function of stimulus significance. In Roy J-C, Boucsein W, Fowles D, Gruzelier J, editors. Progress in Electrodermal Research. New York: Plenum Press, pp 239 –255. Kimble DP, Bagshaw MH, Pribram KH (1965): The GSR of monkeys during orienting and habituation after selective ablations of cingulate and frontal cortex. Neuropsychologia 3:121–128. Lim CL, Rennie C, Barry RJ, Bahramali H, Lazzaro I, Manor B, et al (1997): Decomposing skin conductance into tonic and phasic components. Int J Psychophysiol 25:97–107.
Electrodermal Activity in Schizophrenia
Lockhart RA (1972): Interrelationship between amplitude, latency, rise time, and Edelberg recovery measure of the galvanic skin response. Psychophysiology 9:437– 442. Lykken DT, Venables PH (1971): Direct measurement of skin conductance: A proposal for standardisation. Psychophysiology 8:656 – 672. ¨ hman A (1981): Electrodermal activity and vulnerability to O schizophrenia: A review. Biol Psychol 12:87–145. Parker G, Hadzi-Pavlovic D, Boyce P, Wilhelm K, Brodaty H, Mitchell P, Hicke I, Eyers K (1990): Classifying depression by mental state signs. Brit J Psychiat 157:55– 65. Pribram KH, McGuinness D (1975): Arousal activation and effort in the control of attention. Psychol Rev 82:116 –149. Pritchard WS (1986): Cognitive event-related potential correlates of schizophrenia. Psychol Bull 100:43– 66. Roth WT, Goodale J, Pfefferbaum A (1991): Auditory eventrelated potentials and electrodermal activity in medicated and unmedicated schizophrenics. Biol Psychiatry 29:585–599. Roy J-C, Sequeira H, Delerm B (1993): Cortical and hypothalamo-limbic control of electrodermal responses. In Roy J-C, Boucsein W, Fowles D, Gruzelier J, editors. Progress in Electrodermal Research. New York: Plenum Press, pp 73–92. Sequeira H, Roy J-C (1993): Neural control of electrodermal activity: Spinal and reticular mechanisms. In: Roy J-C, Boucsein W, Fowles D, Gruzelier J, editors. Progress in
BIOL PSYCHIATRY 1999;45:127–135
135
Electrodermal Research. New York: Plenum Press, pp 93– 114. Venables PH (1991): Autonomic activity. In: Zappulla RA, LeFever FF, Jaeger J, Bilder R, editors. Windows on the Brain. New York: New York Academy of Science, pp 191–207. Venables PH (1993): Electrodermal indices as markers for the development of schizophrenia. In: Roy J-C, Boucsein W, Fowles D, Gruzelier J, editors. Progress in Electrodermal Research. New York: Plenum Press, pp 187–205. Venables PH, Christie MJ (1980): Electrodermal activity. In: Martin I, Venables PH, editors. Techniques in Psychophysiology New York: Wiley, pp 3– 67. Wang GH (1964): The Neural Control of Sweating. Madison, WI: University of Wisconsin Press. Wang GH, Lu TW (1930): Galvanic skin reflex induced in the act by stimulation of the motor area of the cerebral cortex. Chin J Physiol 4:303–326. Weinberger DR (1988): Schizophrenia and the frontal lobe. Trends Neurosci 11:367–370. Zahn TP, Pickar D (1993): Autonomic effects of clozapine in schizophrenia: Comparison with placebo and fluphrenazine. Biol Psychiatry 34:3–12. Zahn TP, Carpenter WT, McGlashan TH (1981): Autonomic nervous system activity in acute schizophrenia: I. Method and comparison with normal controls. Arch Gen Psychiatry 38: 251–258.